1. Field of the Invention
Bleomycin is a well-known antitumor antibiotic, commercially available as a mixture of bleomycin species differing only in a terminal amine. While particular species such as bleomycin-A.sub.2 and bleomycin-B.sub.2 have been isolated and characterized, bleomycin is generally employed clinically as a mixture sold under a variety of trademarks such as BLENOXANE (Bristol Laboratories). Bleomycin and its A.sub.2 and B.sub.2 species are characterized in U.S. Pat. No. 4,339,426, issued July 13, 1982 to Meares, et al.
Bleomycin (BLM) has a selective affinity for a variety of tumors, and exerts its cytotoxic effects on susceptible tumor cells by inducing single-strand breaks in the cell DNA. In addition to its role as a chemotherapeutic, BLM has been chelated with a number of radionuclides for use as a radiopharmaceutical or tumor-imaging agent. These chelates have generally a wider application than BLM alone, as BLM does not exhibit cytoxicity against all tumor tissue to which it has a selective affinity; thus the chelates may function as a radiopharmaceutical, combining both radiotherapy and chemotherapy, or the BLM may merely function as a vehicle for targeting the radionuclide on tumor tissue.
2. Description of the Prior Art
Radiolabelled pharmaceuticals for radio-chemotherapy ideally have a high affinity for tumor tissue, deliver a high dosage of radioactivity to the tumor tissue and a minimal dosage to adjacent tissues, and function to sensitize the tissues to radiation. Complexes of .sup.111 Indium (.sup.111 In) with bleomycin mixtures and bleomycin-A.sub.2 or bleomycin-B.sub.2 which approach these criteria have been described. These known .sup.111 In-BLM complexes have a high selective affinity for tumor tissue and are relatively safe. .sup.111 In emits both X-radiation and beta radiation, and bleomycin is believed to function as a radiosensitizer. These two properties are important in radiotherapy. .sup.111 In also strongly emits gamma radiation (gamma energies of 173 and 247 kev), and has an effective half-life of 2.8 days; .sup.111 In-BLM complexes are thus potentially useful as tumor-imaging agents. Unfortunately, however, known bleomycin chelates of .sup.111 In bind to serum transferrin. The body is thus broadly exposed to radiation, and the complex is consequently unsuitable for therapy or for use in tumor-imaging. The BLM chelate of .sup.57 Co has been proposed as an alternative to .sup.111 In-BLM; however, the physical half-life of .sup.57 Co (270 days) makes it clinical use as a diagnostic agent impractical.